Major depressive disorder (MDD) is the most common lifetime mental disorder1 and is associated with tremendous personal, economic and societal costs2, 3. Although existing research has evaluated various genetic, cognitive, and environmental risk factors for MDD4, much prior work has evaluated risk factors in isolation without examining commonalities and incremental ability to predict which individuals will become depressed. This proposal seeks to evaluate and compare inflexible cognitive, behavioral, and psychophysiological factors known to be associated with depression5, and that may also constitute vulnerabilities to depression, particularly in combination with life stressors , 7. The proposed project is designed to more closely examine (1) which measures of cognitive, behavioral, and psychophysiological inflexibility confer the greatest risk for increases in depressive symptoms, particularly when individuals are confronted with life stressors, and (2) whether depressive symptoms predict decreased coping flexibility and explanatory flexibility. Given that the onset of MDD typically occurs between adolescence and early adulthood3, and that the college years are a time of fluctuation in stressors in the academic and interpersonal domains8-10, college may be an ideal period in which to evaluate patterns of coping in response to these stressors11. Therefore, participants in the proposed study will be college students. Participants will complete a baseline evaluation of depressive symptoms, coping flexibility, explanatory flexibility, cognitive flexibility (via behavioral and neuropsychological tasks), and psychophysiological flexibility (via respiratory sinus arrhythmia). Participants will complete four follow-up assessments, once every three weeks, evaluating life stress, explanatory flexibility and coping flexibility in response to life stress experienced, and depressive symptoms, allowing for idiographic (within-subject) measurement of variations in stress12. The multi-method, multi-wave design of this study will allow for powerful assessment and comparison of these inflexibilities and has the potential to illuminate specific facets of inflexibility that may confer the greatest risk for depression. Thus, this study has the potentialto provide a better understanding of the mechanisms involved in the development of MDD, which may help to inform prevention programs for individuals at risk for this condition. PUBLIC HEALTH RELEVANCE: Major depressive disorder (MDD) is the most common lifetime mental disorder and is associated with tremendous personal, economic and societal costs. The proposed project is designed to examine which measures of cognitive, behavioral, and psychophysiological inflexibility confer the greatest risk for depression, particularly when individuals are confronted with life stressors. A better understanding of the mechanisms involved in the development of MDD will help to inform prevention programs for individuals at risk for this condition.